Plasma norepinephrine (NE) and brain natriuretic peptide (BNP, termed BNP-45 in rats) are considered as essential neurohormones indicating heart failure progression. The purposes of this study were to examine the effects of ivabradine () on cardiac function and plasma NE and BNP-45 after chronic ischemic heart failure (CHF) in non-diabetic rats and diabetic rats. We further determined if sympathetic NE uptake-1 (a major pathway to metabolize NE) mechanism is responsible for the role played by .We ligated rat's coronary artery to induce CHF; and injected streptozotocin (STZ) to induce diabetic hyperglycemia. Echocardiography was employed to determine cardiac function. We used ELISA to examine plasma NE and BNP-45; and Western Blot analysis to examine the protein levels of NE uptake-1 in sympathetic nerves.CHF increased the levels of NE and BNP-45 in non-STZ rats and STZ rats. Systemic injection of significantly attenuated the augmented NE and BNP-45 and impaired left ventricular function induced by CHF in those rats. This effect appeared to be less in STZ rats. A liner relation was observed between the NE/BNP-45 levels and left ventricular function after administration of . Also, was observed to have a recovery effect on the downregulated NE uptake-1 evoked by CHF, but to a smaller degree in STZ rats.Our data revealed specific signaling mechanisms by which improves the cardiac function as alleviates impaired NE uptake-1and thereby decreases heightened NE and BNP-45 induced by CHF. Our data also demonstrated that the effects of are weakened after diabetic hyperglycemia likely due to worsen NE uptake-1 pathway. Thus, targeting sympathetic NE uptake-1 signaling molecules has clinical implications for treatment and management of CHF in diabetes. Our data were also to shed light on strategies for application of this drug because NE and BNP play an important role in regulation of progression and prognosis of CHF, and in particular, because affects NE uptake-1 pathway in hyperglycemic animals to a less degree.© 2016 The Author(s) Published by S. Karger AG, Basel.
Keyword: IBD
The predominance of specific bacteria such as adherent-invasive Escherichia coli (AIEC) within the Crohn's disease (CD) intestine remains poorly understood with little evidence uncovered to support a selective pressure underlying their presence. Intestinal is however readily accessible during periods of intestinal inflammation, and enables pathogens to outcompete the host microbiota under such circumstances.Quantitative RT-PCR (qRT-PCR) to determine expression of genes central to metabolism; transmission electron microscopy to detect presence of bacterial microcompartments (MCPs); in vitro infections of both murine and human macrophage cell lines examining intracellular replication of the AIEC-type strain LF82 and clinical E. coli isolates in the presence of ; determination of E. coli utilization (eut) operon transcription in faecal samples from healthy patients, patients with active CD and the same patients in remission following treatment.Growth on the intestinal short chain fatty acid propionic acid (PA) stimulates significantly increased transcription of the eut operon (fold change relative to glucose: >16.9; p-value <.01). Additionally was accessible to intra-macrophage AIEC and stimulated significant increases in growth intracellularly when it was added extracellularly at concentrations comparable to those in the human intestine. Finally, qRT-PCR indicated that expression of the E. coli eut operon was increased in children with active CD compared to healthy controls (fold change increase: >4.72; P\u202f<\u202f.02). After clinical remission post-exclusive enteral nutrition treatment, the same CD patients exhibited significantly reduced eut expression (Pre vs Post fold change decrease: >15.64; P\u202f<\u202f.01).Our data indicates a role for metabolism in selecting for AIEC that are consistently overrepresented in the CD intestine. The increased E. coli metabolism of seen in the intestine during active CD, and its decrease during remission, indicates use may be a key factor in shaping the intestinal microbiome in CD patients, particularly during times of inflammation. FUND: This work was funded by Biotechnology and Biological Sciences Research Council (BBSRC) grants BB/K008005/1 & BB/P003281/1 to DMW; by a Tenovus Scotland grant to MJO; by Glasgow Children's Hospital Charity, Nestle Health Sciences, Engineering and Physical Sciences Research Council (EPSRC) and Catherine McEwan Foundation grants awarded to KG; and by a Natural Environment Research Council (NERC) fellowship (NE/L011956/1) to UZI. The team at the Royal Hospital for Children, Glasgow are supported by the Catherine McEwan Foundation and Yorkhill fund. RKR and RH are supported by NHS Research Scotland Senior fellowship awards.Copyright © 2019. Published by Elsevier B.V.
Keyword: IBD
Inflammatory bowel diseases () are associated with compositional and functional changes of the intestinal microbiota, but specific contributions of individual bacteria to chronic intestinal inflammation remain unclear. is a resident member of the human intestinal core microbiota that has been linked to the pathogenesis of and induces chronic colitis in susceptible monoassociated IL-10-deficient (IL-10) mice. In this study, we characterized the colitogenic activity of as part of a simplified human microbial consortium based on seven enteric bacterial strains (SIHUMI). RNA sequencing analysis of isolated from monoassociated wild type and IL-10 mice identified 408 genes including 14 genes of the utilization () locus that were significantly up-regulated in response to inflammation. Despite considerable up-regulation of genes, deletion of utilization (Δ) had no impact on colitogenic activity in monoassociated IL-10 mice. However, replacement of the wild type bacteria by a Δ mutant in SIHUMI-colonized IL-10 mice resulted in exacerbated colitis, suggesting protective functions of utilization in complex bacterial communities. To better understand gene response in the presence of other microbes, we purified wild type cells from the colon content of SIHUMI-colonized wild type and IL-10 mice using immuno-magnetic separation and performed RNA sequencing. Transcriptional profiling revealed that the bacterial environment reprograms gene expression in response to inflammation, with the majority of differentially expressed genes not being shared between monocolonized and SIHUMI conditions. While in monoassociation a general bacterial stress response could be observed, expression of genes in SIHUMI-colonized mice was characterized by up-regulation of genes involved in growth and replication. Interestingly, in mice colonized with SIHUMI lacking enhanced inflammation was observed in comparison to SIHUMI-colonized mice, supporting the hypothesis that metabolism protects against colitis in complex consortia. In conclusion, this study demonstrates that complex bacterial consortia interactions reprogram the gene expression profile and colitogenic activity of the opportunistic pathogen toward a protective function.
Keyword: IBD
Angiogenesis is emerging as a pivotal process in chronic inflammatory pathologies, promoting immune infiltration and prompting carcinogenesis. Ulcerative Colitis (UC) and Crohn's Disease (CD) represent paradigmatic examples of intestinal chronic inflammatory conditions in which the process of neovascularization correlates with the severity and progression of the diseases. Molecules able to target the angiogenesis have thus the potential to synergistically affect the disease course. Beyond its anti-inflammatory effect, palmitoylethanolamide (PEA) is able to reduce angiogenesis in several chronic inflammatory conditions, but no data about its anti-angiogenic activity in colitis have been produced, yet.The effects of PEA on inflammation-associated angiogenesis in mice with dextran sulphate sodium (DSS)-induced colitis and in patients with UC were assessed. The release of Vascular Endothelial Growth Factor (VEGF), the hemoglobin tissue content, the expression of CD31 and of phosphatidylinositol 3-kinase/Akt/mammalian-target-of-rapamycin (mTOR) signaling axis were all evaluated in the presence of different concentrations of PEA and concomitant administration of PPAR-α and -γ antagonists.Our results demonstrated that PEA, in a selective peroxisome proliferator activated receptor (PPAR)-α dependent mechanism, inhibits colitis-associated angiogenesis, decreasing VEGF release and new vessels formation. Furthermore, we demonstrated that the mTOR/Akt axis regulates, at least partly, the angiogenic process in and that PEA directly affects this pathway.Our results suggest that PEA may improve inflammation-driven angiogenesis in colonic mucosa, thus reducing the mucosal damage and potentially affecting disease progression and the shift towards the carcinogenesis.
Keyword: IBD
The human gut is a composite anaerobic environment with a large, diverse and dynamic enteric microbiota, represented by more than 100 trillion microorganisms, including at least 1000 distinct species. The discovery that a different microbial composition can influence behavior and cognition, and in turn the nervous system can indirectly influence enteric microbiota composition, has significantly contributed to establish the well-accepted concept of gut-brain axis. This hypothesis is supported by several evidence showing mutual mechanisms, which involve the vague nerve, the immune system, the hypothalamic-pituitaryadrenal (HPA) axis modulation and the bacteria-derived metabolites. Many studies have focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disorders, such as autism, and to neurodegenerative diseases, such as Parkinson Disease, Alzheimer's Disease etc. Based on this background, and considering the relevance of alteration of the symbiotic state between host and microbiota, this review focuses on the role and the involvement of bioactive lipids, such as the N-acylethanolamine (NAE) family whose main members are N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, belonging to a large group of bioactive lipids able to modulate peripheral and central pathologic processes. Their effective role has been studied in inflammation, acute and chronic pain, obesity and central nervous system diseases. A possible correlation has been shown between these lipids and gut microbiota through different mechanisms. Indeed, systemic administration of specific bacteria can reduce abdominal pain through the involvement of cannabinoid receptor 1 in the rat; on the other hand, PEA reduces inflammation markers in a murine model of inflammatory bowel disease (), and butyrate, producted by gut microbiota, is effective in reducing inflammation and pain in irritable bowel syndrome and animal models. In this review, we underline the relationship among inflammation, pain, microbiota and the different lipids, focusing on a possible involvement of NAEs and SCFAs in the gut-brain axis and their role in the central nervous system diseases.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Keyword: IBD
Inflammatory bowel disease [] is considered to result from the interplay between host and intestinal microbiota but its pathogenesis is incompletely understood. While in adults has shown to be associated with marked changes in body fluid metabolomics, there are only few studies in children. Hence, this prospective study addressed the faecal and serum metabolomics in newly diagnosed paediatric .Paediatric patients with undergoing diagnostic endoscopies and controls also with endoscopy but no signs of inflammation provided blood and stool samples in a tertiary care hospital. Blood inflammatory markers and faecal calprotectin levels were determined. The serum and faecal metabolomics were determined using ultra-high pressure liquid chromatography coupled to a mass spectrometer.Serum and faecal metabolite profiles in newly diagnosed paediatric patients were different from healthy controls and categorized Crohn's disease and ulcerative colitis [UC] patients into separate groups. In serum, amino acid metabolism, folate biosynthesis and signalling pathways were perturbed in Crohn's disease; in UC also sphingolipid metabolic pathways were perturbed when compared to controls. In faecal samples, there was an increased level of several metabolites in UC in contrast to low or intermediate levels in Crohn's disease. There was a clear correlation with the level of inflammation, i.e. faecal calprotectin levels and the profile of various biologically important metabolites [carnosine, ribose and, most significantly, choline].Characterization of inflammatory pattern using metabolomics analysis is a promising tool for better understanding disease pathogenesis of paediatric .Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
Keyword: IBD
Fatty acid amides (FAAs), conjugates of fatty acids with , mono-amine neurotransmitters or amino acids are a class of molecules that display diverse functional roles in different cells and tissues. Recently we reported that one of the serotonin-fatty acid conjugates, docosahexaenoyl serotonin (DHA-5-HT), previously found in gut tissue of mouse and pig, attenuates the IL-23-IL-17 signaling axis in LPS-stimulated mice macrophages. However, its presence and effects in humans remained to be elucidated. Here, we report for the first time its identification in human intestinal (colon) tissue, along with a series of related N-acyl serotonins. Furthermore, we tested these fatty acid conjugates for their ability to inhibit the release of IL-17 and CCL-20 by stimulated human peripheral blood mononuclear cells (PBMCs). Serotonin conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT) and oleic acid (OA-5-HT) were detected in higher levels than arachidonoyl serotonin (AA-5-HT) and DHA-5-HT, while eicosapentaenoyl serotonin (EPA-5-HT) could not be quantified. Among these, DHA-5-HT was the most potent in inhibiting IL-17 and CCL-20, typical Th17 pro-inflammatory mediators, by Concanavalin A (ConA)-stimulated human PBMCs. These results underline the idea that DHA-5-HT is a gut-specific endogenously produced mediator with the capacity to modulate the IL-17/Th17 signaling response. Our findings may be of relevance in relation to intestinal inflammatory diseases like Crohn's disease and Ulcerative colitis.Copyright © 2017. Published by Elsevier B.V.
Keyword: IBD
Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100-500nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease () and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. or intestinal tumorigenesis.Copyright © 2016 Elsevier B.V. All rights reserved.
Keyword: IBD
N-Palmitoylethanolamine or palmitoylethanolamide (PEA) is an anti-inflammatory compound that was recently shown to exert peroxisome proliferator-activated receptor-α-dependent beneficial effects on colon inflammation. The actions of PEA are terminated following hydrolysis by 2 enzymes: fatty acid amide hydrolase (FAAH), and the less-studied N-acylethanolamine-hydrolyzing acid amidase (NAAA). This study aims to investigate the effects of inhibiting the enzymes responsible for PEA hydrolysis in colon inflammation in order to propose a potential therapeutic target for inflammatory bowel diseases (IBDs). Two murine models of were used to assess the effects of NAAA inhibition, FAAH inhibition, and PEA on macroscopic signs of colon inflammation, macrophage/neutrophil infiltration, and the expression of proinflammatory mediators in the colon, as well as on the colitis-related systemic inflammation. NAAA inhibition increases PEA levels in the colon and reduces colon inflammation and systemic inflammation, similarly to PEA. FAAH inhibition, however, does not increase PEA levels in the colon and does not affect the macroscopic signs of colon inflammation or immune cell infiltration. This is the first report of an anti-inflammatory effect of a systemically administered NAAA inhibitor. Because NAAA is the enzyme responsible for the control of PEA levels in the colon, we put forth this enzyme as a potential therapeutic target in chronic inflammation in general and in particular.© FASEB.
Keyword: IBD
We sought to quantify the anti-inflammatory effects of two cannabinoid drugs, cannabidiol (CBD) and palmitoylethanolamide (PEA), in cultured cell lines and compared this effect with experimentally inflamed explant human colonic tissue. These effects were explored in acutely and chronically inflamed colon, using inflammatory bowel disease and appendicitis explants.Caco-2 cells and human colonic explants collected from elective bowel cancer, inflammatory bowel disease () or acute appendicitis resections, and were treated with the following drug treatments: vehicle, an inflammatory protocol of interferon γ (IFNγ) and tumour necrosis factor α (TNFα; 10 ng/ml), inflammation and PEA (10 µM), inflammation and CBD (10 µM), and PEA or CBD alone, CBD or vehicle were added simultaneously with IFNγ. Nine intracellular signalling phosphoproteins were determined by multiplex. Inflammatory cytokine secretion was determined using ELISA. Receptor mechanisms were investigated using antagonists for CB, CB, PPARα, PPARγ, TRPV1 and GPR55.IFNγ and TNFα treatment increased phosphoprotein and cytokine levels in Caco-2 cultures and colonic explants. Phosphoprotein levels were significantly reduced by PEA or CBD in Caco-2 cultures and colonic explants. CBD and PEA prevented increases in cytokine production in explant colon, but not in Caco-2 cells. CBD effects were blocked by the CB antagonist AM630 and TRPV1 antagonist SB366791. PEA effects were blocked by the PPARα antagonist GW6471. PEA and CBD were anti-inflammatory in and appendicitis explants.PEA and CBD are anti-inflammatory in the human colon. This effect is not seen in cultured epithelial cells. Appropriately sized clinical trials should assess their efficacy.© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
Keyword: IBD